Semisynthetic Analogs of the Antibiotic Fidaxomicin—Design, Synthesis, and Biological Evaluation
| Autor: | Daniel Schäfle, Andrea Dorst, Peter Sander, Christoph G. W. Gertzen, Holger Gohlke, Karl Gademann, Regina Berg, Simon D. Schnell, Myriam Gwerder, Katja Zerbe |
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| Rok vydání: | 2020 |
| Předmět: |
Letter
medicine.drug_class homology modeling Antibiotics 01 natural sciences Biochemistry antibiotics Lipiarmycin A3 chemistry.chemical_compound Drug Discovery medicine semisynthesis Fidaxomicin ddc:610 Biological evaluation water solubility Natural product biology 010405 organic chemistry Organic Chemistry biology.organism_classification Semisynthesis Combinatorial chemistry 3. Good health 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Design synthesis Bacteria medicine.drug |
| Zdroj: | ACS medicinal chemistry letters 11(12), 2414–2420 (2020). doi:10.1021/acsmedchemlett.0c00381 ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00381 |
| Popis: | The glycoslated macrocyclic antibiotic fidaxomicin (1, tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of Clostridium difficile infections (CDI). Among the main limitations for this compound, its low water solubility impacts further clinical uses. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product. An increase in solubility of up to 25-fold with largely retained activity was observed. Furthermore, hybrid antibiotics were prepared that show improved antibiotic activities. |
| Databáze: | OpenAIRE |
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